Iron-deficiency anemia is referred to as microcytic hypochromic anemia, one of the most popular anemia throughout the world, which is caused by insufficient iron storage in the body to an extent that affects the synthesis of hemoglobin.
Iron deficiency may be caused by various factors, such as insufficient iron intake, increased iron consumption, excessive loss of iron, poor absorption of iron, or increased loss of free iron, etc. The most effective way for treating iron deficiency anemia is to replenish iron. The way of replenishing iron comprises oral iron supplementation which are generally iron salts of a small molecular weight, such as ferrous sulfate, ferrous gluconate, ferrous lactate and the like; or parenteral iron which are typically complexes of iron and a saccharide, including polysaccharide, oligosaccharide, or monosaccharide, such as iron dextran, iron sucrose (published in the current USP and the Chinese Pharmacopoeia), and sodium ferric gluconate, due to their good solubility and relatively low toxicity upon parenteral administration.
Although oral administration of iron is the major way for iron replenishment, sometimes it is especially advantageous to parenteral iron supplementation, for example, when oral administration of iron is inappropriate, oral iron therapy is ineffective, or there is an urgent need of rapidly correcting iron deficiency anemia. In particular, parenteral iron is being used more and more often to replace oral administration in treating renal anemia. As reported in the clinical practice guidelines for the treatment of anemia of chronic renal failure made by the U.S. National Kidney Foundation Dialysis Outcome Quality Initiative, NKF-DOQI in 1997: “When Epoetin is administered to a patient of chronic kidney dysfunction (CKD), it is necessary to maintain the value of Ht to 33-36% (corresponding to a level of Hb of 11-12 g/dl), thus supplemental iron should be administered to prevent iron deficiency and to maintain adequate iron storage. Oral administration of iron cannot maintain a sufficient level of iron in adult patients before hemodialysis, home hemodialysis patients, and peritoneal dialysis (PD) patients in vivo. Iron may be orally administered to a hemodialysis patient, but it is unlikely for the patient to maintain a TSAT of above 20%, serum ferritin at a level higher than 100 ng/mL, and an Ht value of 33% to 36% (an Hb level of 11 to 12 g/dL). To achieve and maintain an Ht value of 33% to 36% (an Hb level of 11 to 12 g/dL), most hemodialysis patients will require intravenous iron injection on a regular basis.” However, the use of iron dextran will cause dosage-independent allergic response (0.7%-1%) that even seriously threatens the lives of patients. In 1991-1999, more than 30 patients died of allergic responses to iron dextran. While, the incidence rate of severe allergy caused by administration of iron sucrose and sodium ferric gluconate is apparently lower than that caused by administration of iron dextran. Among 450,000 patients who had been treated with iron sucrose injection of the trade name of Venofer® during 1992-1999, 27 cases were reported to exhibit an allergic reaction, of which only 8 cases were serious (http://www.hcfa.gov/coverage/8b3-11.htm), thus iron dextran is gradually being replaced by iron sucrose.
The polynuclear ferric hydroxide-saccharide complexes being referred to herein do not include complexes of high molecular weight polysaccharide such as dextran and ferric hydroxides, unless specifically indicated otherwise in the context.
Iron sucrose is a polynuclear ferric hydroxides-sucrose complex having a high molecular weight, and the relative molecular weight Mw (weight-average molecular weight) of a commercially available product (Venofer®) is 34000-60000 Daltons. Some literatures reported that the molecular weights of iron-saccharide complexes are relevant to their pharmacodynamic parameters and side effects such as allergy during their clinic application. If their molecular weights are too high or too low, they will cause adverse effects. Therefore, for such iron-saccharide complexes, it is quite important to control their molecular weight within a suitable range so as to ensure the safety and effectiveness in their clinical application as well as the quality homogeneity of the product. The specifications for iron sucrose injection is recorded in the 27th version of USP, which species the range of the relative molecular weight of iron sucrose (Mw 34000-60000 Daltons, Mw/Mn<1.7, Mn being the number-average molecular weight) and methods for the determination thereof.
However, although the iron sucrose has been marketed for many years, there are few reports on its preparation methods. Nissim (The Lancet Apr. 23, 1949 p 686-689) disclosed a method for preparing iron sucrose, and mentioned the control of the isoelectric point of iron sucrose. It demonstrated that the toxicity of iron sucrose increased when the isoelectric point was too high or too low, yet it did not mention the control of the molecular weight thereof. In the specifications for iron sucrose injection liquid embodied in 27th version of USP, the isoelectric point is specified as 4.4-5.3.
Patent publication No. WO 2005000210 described a method for preparing an iron-saccharide complex with an absolute molecular weight of above 25,000 Daltons, wherein an aqueous solution or dispersion containing iron ions and hydroxyl ions is heated together with a saccharide under an alkaline condition for a given time to allow the iron-saccharide complex to reach a desired molecular weight. However, except that the absolute molecular weight of the resulting complex was determined therein, the preparation process disclosed therein has no significant difference from that recited in the published literatures. Neither did WO 2005000210 disclose how to control the molecular weight of the complex more accurately or how to control its isoelectric point. Therefore, those skilled in the art can neither produce products which meet the requirements of the USP nor ensure the safety of the products in accordance with the techniques disclosed in WO 2005000210.
In the published patent application No. WO 2005000210, the molecular weight of the iron-saccharide complex is controlled by heating a mixture of iron and a saccharide under an alkaline condition for a given time until a desired molecular weight is reached. Specifically, WO 2005000210 teaches that, where the molecular weight of the complex is higher than that desired, excess saccharide may be added to lower it. However, this is disadvantageous during the drug manufacturing process because the addition will change the content of the saccharide in the product, which has to be restricted to a specific range, for example, from 26% to 34% as stipulated in the 27th version of USP. Apparently, the method as disclosed in WO 2005000210 has a limited ability to control the range of the molecular weight of the product. Furthermore, in WO 2005000210, it is also mentioned that, when the iron-saccharide mixture is heated to a temperature of aggregation-point, the molecular weight of the product will tend to increase or decrease over time depending on the difference in the content of the saccharide in the product. Clearly, it will be difficult for the process to be used for preparing an iron-saccharide complex with a high molecular weight when the content of the saccharide is high.